Prediction of Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Development and Validation of a Pretreatment Nomogram

Abstract

Introduction: In patients with esophageal cancer, occurrence of severe radiation-induced lymphopenia during chemoradiation therapy has been associated with worse progression-free and overall survival. The aim of this study was to develop and validate a pretreatment clinical nomogram for the prediction of grade 4 lymphopenia. Methods and Materials: A development set of consecutive patients who underwent chemoradiation therapy for esophageal cancer and an independent validation set of patients from another institution were identified. Grade 4 lymphopenia was defined as an absolute lymphocyte count nadir during chemoradiation therapy of <0.2 Â 10 3 /mL. Multivariable logistic regression analysis was used to create a prediction model for grade 4 lymphopenia in the development set, which was internally validated using bootstrapping and externally validated by applying the model to the validation set. The model was presented as a nomogram yielding 4 risk groups. Results: Among 860 included patients, 322 (37%) experienced grade 4 lymphopenia. Higher age, larger planning target volume in interaction with lower body mass index, photon-rather than proton-based therapy, and lower baseline absolute lymphocyte count were predictive in the final model (corrected c-statistic, 0.76). External validation in 144 patients, among whom 58 (40%) had grade 4 lymphopenia, yielded a c-statistic of 0.71. Four nomogram-based risk groups yielded predicted risk rates of 10%, 24%, 43%, and 70%, respectively.

The Impact of Radiotherapy Parameters on Lymphopenia and Overall Survival in Patients With Esophageal Cancer

“…Multivariate analysis identi ed low TLC and high NLR before the treatment as predicting inferior survival. In recent preclinical study, the grade 4 lymphopenia seemed to predict the worse progression-free and overall survival in esophageal cancer cohort (17) . In this study, we demonstrated that pretreatment NLR and ALC nadir during de nitive RT were signi cantly associated with worse outcomes.…”

Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy With Immunotherapy

“…Taking into account the negative effect of LP on clinical outcomes, it is important to identify high-risk patients timely and possibly adapt the treatment. Models predicting grade 4 RT-induced LP during chemo (radio) therapy for esophageal cancer, or acute and late LP for prostate cancer have already been published, 70,71 although the prostate model is yet to be validated. 19,72 Also for NSCLC, a predictive risk model has been developed where clinical and genetic factors, for example, lung V5 > 48%, age >65 years, >40 pack-years, and XRCC1 rs25487 AA genotype, are associated with severe RT-induced LP.…”

Bystander Effects and Unintended Consequences: Time to Include the Spleen in Radiation Therapy Planning

“…For esophageal cancer chemoradiation, higher spleen dose is associated with a higher risk of lymphopenia in one study and lower toxicity in another ( 11 , 12 ). Distal esophageal cancers and larger irradiated volumes are more likely to have severe lymphopenia, suggesting lower dose to normal tissue may matter ( 13 , 14 ). Lymphopenia is also associated with lower survival ( 13 ).…”

“…Distal esophageal cancers and larger irradiated volumes are more likely to have severe lymphopenia, suggesting lower dose to normal tissue may matter ( 13 , 14 ). Lymphopenia is also associated with lower survival ( 13 ). Similar data are emerging in pancreatic cancer chemoradiation ( 15 – 18 ), with lower rates of lymphopenia using stereotactic body techniques ( 19 , 20 ).…”

“…The spleen also may play an important role in effective cancer treatment, especially in the immunotherapy era ( 27 ). Treatment-related lymphopenia is associated with worse disease progression and survival in esophageal, pancreatic, and lung cancer ( 13 , 16 , 28 – 30 ). The spleen is an important source of tumor-associated macrophages and neutrophils ( 31 ), which may contribute to tumor progression and death via decreased immune surveillance or pro-inflammatory stimulation for tumor growth ( 32 – 37 ).…”